Δ9-Tetrahydrocannabinol antagonizes endocannabinoid modulation of synaptic transmission between hippocampal neurons in culture

Cannabinoids inhibit excitatory synaptic transmission between hippocampal neurons in culture. Delta(9)-tetrahydrocannabinol (THC), the principal psychoactive component in marijuana, acts as a partial agonist at these synapses. Thus. THC inhibited but did not block synaptic transmission when applied alone and, when applied in combination with WIN552212-2, it partially reversed the effects of this full agonist. Here, we address the question of how THC might interact with endocannabinoid signaling. Reducing the extracellular Mg2+ concentration to 0.1 mM elicited a repetitive pattern of glutamatergic synaptic activity that produced intracelllar Ca2+ concentration spikes that were measured by indo-1-based microfluorimetry. The endocannabinoid, 2-arachidonyl glycerol (2-AG) produced a concentration-dependent and complete inhibition of spike frequency with an EC50 Of 63 +/- 13 nM. 2-AG (1 muM) inhibition of spiking was blocked by SR141716A (1 muM). THC (100 nM) antagonized the actions of 2-AG producing a parallel shift in the concentration-response relationship for 2-AG (EC50 of 1430 +/- 254 nM). The attenuation of 2-AG (1 muM) inhibition of synaptic activity by THC was concentratiori-clependent with ail THC of 42 +/- 9 nM. These results demonstrate that THC can antagonize endocannabinoid signaling. Thus, the effects of THC on synaptic transmission are predicted to depend on the level of endocannabinoid tone. (C) 2004 Elsevier Ltd. All rights reserved.